Empowering Older Antibiotics.

Avycaz combines an older cephalosporin antibiotic, ceftazidime, and the ß-lactamase inhibitor avibactam. Ceftazidime targets penicillin-binding proteins (PBPs) in the bacterial periplasm that are required for cell wall synthesis. Avibactam blocks ß-lactamases (ß-L) in the periplasm, which would otherwise inactivate the antibiotics resulting in drug resistance.

Sequential Treatment Failure With Aztreonam-Ceftazidime-Avibactam Followed by Cefiderocol Due to Preexisting and Acquired Mechanisms in a New Delhi Metallo-ß-lactamase-Producing Escherichia coli Causing Fatal Bloodstream Infection.

We report a fatal case of New Delhi metallo-ß-lactamase (NDM)-producing Escherichia coli in a bacteremic patient with sequential failure of aztreonam plus ceftazidime-avibactam followed by cefiderocol. Acquired resistance was documented phenotypically and mediated through preexisting and acquired mutations. This case highlights the need to rethink optimal treatment for NDM-producing organisms.

Emergence of cefiderocol resistance during ceftazidime/avibactam treatment caused by a large genomic deletion, including ampD and piuCD genes, in Pseudomonas aeruginosa.

We report the emergence of cefiderocol resistance during the treatment of a ST312 Pseudomonas aeruginosa respiratory infection with ceftazidime/avibactam. whole genome sequencing (WGS) revealed that resistance was caused by a large genomic deletion, including PiuDC (iron transport system) and AmpD (ampC negative regulator), driven by the integration of phage DNA. Thus, our findings alert that this type of deletion could be an efficient (two mechanisms in one step) specific cefiderocol resistance mechanism that might occur nonspecifically upon treatment with ß-lactams that select for AmpC overexpression.

Difficult-to-treat (DTR) Pseudomonas aeruginosa harboring Verona-Integron metallo-ß-lactamase (blaVIM): infection management and molecular analysis.

Pseudomonas aeruginosa harboring Verona Integron-encoded metallo-ß-lactamase enzymes (VIM-CRPA) have been associated with infection outbreaks in several parts of the world. In the US, however, VIM-CRPA remain rare. Starting in December 2018, we identified a cluster of cases in our institution. Herein, we present our epidemiological investigation and strategies to control/manage these challenging infections. This study was conducted in a large academic healthcare system in Miami, FL, between December 2018 and January 2022. Patients were prospectively identified via rapid molecular diagnostics when cultures revealed carbapenem-resistant P. aeruginosa. Alerts were received in real time by the antimicrobial stewardship program and infection prevention teams. Upon alert recognition, a series of interventions were performed as a coordinated effort. A retrospective chart review was conducted to collect patient demographics, antimicrobial therapy, and clinical outcomes. Thirty-nine VIM-CRPA isolates led to infection in 21 patients. The majority were male (76.2%); the median age was 52 years. The majority were mechanically ventilated (n = 15/21; 71.4%); 47.6% (n = 10/21) received renal replacement therapy at the time of index culture. Respiratory (n = 20/39; 51.3%) or bloodstream (n = 13/39; 33.3%) were the most common sources. Most infections (n = 23/37; 62.2%) were treated with an aztreonam-avibactam regimen. Six patients (28.6%) expired within 30 days of index VIM-CRPA infection. Fourteen isolates were selected for whole genome sequencing. Most of them belonged to ST111 (12/14), and they all carried blaVIM-2 chromosomally. This report describes the clinical experience treating serious VIM-CRPA infections with either aztreonam-ceftazidime/avibactam or cefiderocol in combination with other agents. The importance of implementing infection prevention strategies to curb VIM-CRPA outbreaks is also demonstrated.

The pharmacokinetics/pharmacodynamics of ceftazidime/avibactam for central nervous system infections caused by carbapenem-resistant Gram-negatives: a prospective study.

OBJECTIVES: To describe the pharmacokinetics/pharmacodynamics (PK/PD) of ceftazidime/avibactam in critically ill patients with CNS infections. METHODS: A prospective study of critically ill patients with CNS infections who were treated with ceftazidime/avibactam and the steady-state concentration (Css) of ceftazidime/avibactam in serum and/or CSF was conducted between August 2020 and May 2023. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of ceftazidime/avibactam was evaluated. RESULTS: Seven patients were finally included. The ceftazidime/avibactam target attainment in plasma was optimal for three, quasi-optimal for one and suboptimal for three. In three patients with CSF drug concentrations measured, ceftazidime/avibactam target attainment in CSF was 100% (3/3), which was optimal. The AUCCSF/serum values were 0.59, 0.44 and 0.35 for ceftazidime and 0.57, 0.53 and 0.51 for avibactam. Of the seven patients, 100% (7/7) were treated effectively, 71.4% (5/7) achieved microbiological eradication, 85.7% (6/7) survived and 14.3% (1/7) did not survive. CONCLUSIONS: The limited clinical data suggest that ceftazidime/avibactam is effective in the treatment of CNS infections caused by MDR Gram-negative bacilli (MDR-GNB), can achieve the ideal drug concentration of CSF, and has good blood-brain barrier penetration.

Clinical outcomes in patients infected with ertapenem-only-resistant Enterobacterales versus multi-carbapenem-resistant Enterobacterales.

BACKGROUND: Use of anti-carbapenem-resistant Enterobacterales (anti-CRE) agents such as ceftazidime/avibactam has been associated with improved clinical outcome in cohorts that primarily include patients infected with CRE that are resistant to meropenem (MCRE). OBJECTIVES: To clarify whether patients with CRE resistant to ertapenem but susceptible to meropenem (ertapenem-only-resistant Enterobacterales; EORE) benefit from therapy with anti-CRE agents. METHODS: Patients treated for CRE infection in hospitals in the USA between 2016 and 2019 and enrolled in the CRACKLE-2 study were included. The primary outcome was the desirability of outcome ranking (DOOR) assessed at 30 days after index cultures. RESULTS: The EORE group included 213 patients and the MCRE group included 643. The demographics were similar between the groups except for the patients' race and origin before admission. The MCRE group received anti-CRE agents for definitive therapy significantly more frequently compared with the EORE group (30% versus 5% for ceftazidime/avibactam). We did not observe a significant difference between the groups in the adjusted DOOR probability of a more desirable outcome for a randomly selected patient in the EORE group compared with the MCRE group (52.5%; 95% CI, 48.3%-56.7%). The MCRE group had a similar proportion of patients who died at 30 days (26% versus 21%) and who were discharged to home (29% versus 40%), compared with the EORE group. CONCLUSIONS: Patients with clinical EORE infection rarely received anti-CRE agents, but attained similar outcomes compared with patients with MCRE infection. The findings support current IDSA treatment guidance for meropenem- or imipenem-based therapy for treatment of EORE infections.

Synergistic effects of ceftazidime/avibactam combined with meropenem in a murine model of infection with KPC-producing Klebsiella pneumoniae.

OBJECTIVES: The emergence and expansion of carbapenem-resistant Klebsiella pneumoniae infections is a concern due to the lack of 'first-line' antibiotic treatment options. The ceftazidime/avibactam is an important clinical treatment for carbapenem-resistant K. pneumoniae infections but there is an increasing number of cases of treatment failure and drug resistance. Therefore, a potential solution is combination therapies that result in synergistic activity against K. pneumoniae carbapenemase: producing K. pneumoniae (KPC-Kp) isolates and preventing the emergence of KPC mutants resistant to ceftazidime/avibactam are needed in lieu of novel antibiotics. METHODS: To evaluate their synergistic activity, antibiotic combinations were tested against 26 KPC-Kp strains. Antibiotic resistance profiles, molecular characteristics and virulence genes were investigated by susceptibility testing and whole-genome sequencing. Antibiotic synergy was evaluated by in vitro chequerboard experiments, time-killing curves and dose-response assays. The mouse thigh model was used to confirm antibiotic combination activities in vivo. Additionally, antibiotic combinations were evaluated for their ability to prevent the emergence of ceftazidime/avibactam resistant mutations of blaKPC. RESULTS: The combination of ceftazidime/avibactam plus meropenem showed remarkable synergistic activity against 26 strains and restored susceptibility to both the partnering antibiotics. The significant therapeutic effect of ceftazidime/avibactam combined with meropenem was also confirmed in the mouse model and bacterial loads in the thigh muscle of the combination groups were significantly reduced. Furthermore, ceftazidime/avibactam plus meropenem showed significant activity in preventing the occurrence of resistance mutations. CONCLUSIONS: Our results indicated that the combination of ceftazidime/avibactam plus meropenem offers viable therapeutic alternatives in treating serious infections due to KPC-Kp.

Ceftazidime/avibactam serum concentration in patients on ECMO.

OBJECTIVES: The use of extracorporeal membrane oxygenation (ECMO) may alter blood levels of several drugs, including antibiotics, leading to under dosing of these drugs and thus to potential treatment failure. No data exist on pharmacokinetics of new antimicrobial, in particular ceftazidime/avibactam. We therefore perform this study to evaluate ceftazidime/avibactam blood levels in ECMO patients and find factors associated with underdosing. METHODS: Retrospective observational study of patients on ECMO having received ceftazidime/avibactam and in whom trough blood levels of ceftazidime and avibactam were available. Main outcome measurement was the number of patients with ceftazidime and avibactam blood levels above predefined cut-off values, derived from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa, namely 8 mg/L for ceftazidime and 4 mg/L for avibactam, and explored factors associated with underdosing. RESULTS: Twenty-three ceftazidime/avibactam trough levels were available in 14 ECMO patients, all of them having received veno-venous ECMO for SARS-CoV-2-associated pneumonia. Although ceftazidime levels were above 8 mg/L in all except one patient, nine (39%) of the avibactam dosages were below 4 mg/L. Increased renal clearance (creatinine clearance > 130 mL/min) was the main factor associated with under dosing, since 7 out of the 10 dosages below the predefined cut-offs were measured in patients with this condition. CONCLUSIONS: In ECMO patients receiving ceftazidime/avibactam, ceftazidime and avibactam serum levels are above EUCAST breakpoints in most cases, justifying the use of normal dosing in ECMO patients. Increased renal clearance may lead to ceftazidime and avibactam under dosing.

Evaluation of the MTS™ aztreonam-avibactam strip (Liofilchem) on New Delhi metallo-ß-lactamase-producing Enterobacterales.

The combination of ceftazidime-avibactam (CAZ-AVI) and aztreonam (ATM) is used to treat MBL-producing Enterobacterales-related infections. The new combination aztreonam-avibactam (AZA) is currently in development. We compared results obtained with the new MIC test strip (MTS) AZA (Liofilchem) with broth microdilution method (BMD) on 41 MBL-producing Enterobacterales from 41 clinical samples. The MTS AZA was also compared to combination testing method using CAZ-AVI and ATM strips. Compared to BMD, categorical agreement (CA) was 100%. Compared with combination testing method, CA was 97.6%. The MTS AZA can be used to determine MICs levels of AZA or CAZ-AVI/ATM combinations.

Prevalence and mortality of ceftazidime/avibactam-resistant KPC-producing Klebsiella pneumoniae bloodstream infections (2018-2022).

INTRODUCTION: Ceftazidime/avibactam-resistance in Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) is a topic of great interest for epidemiological, diagnostic, and therapeutical reasons. However, data on its prevalence and burden on mortality in patients with bloodstream infection (BSI) are lacking. This study was aimed at identifying risk factors for mortality in patients suffering from ceftazidime/avibactam-resistant KPC-Kp BSI. METHODS: An observational retrospective study (January 2018-December 2022) was conducted at a tertiary hospital including all consecutive hospitalized adult patients with a ceftazidime/avibactam-resistant KPC-Kp BSI. Data on baseline clinical features, management, and admission outcomes were analyzed. RESULTS: Over the study period, among all the KPC-Kp BSI events recorded, 38 (10.5%) were caused by ceftazidime/avibactam-resistant KPC-Kp strains, 37 events being finally included. The ceftazidime/avibactam-resistant KPC-Kp strains revealed susceptibility restoration to at least one carbapenem in more than 60% of cases. In-hospital and 30-day all-cause mortality rates were 22% and 16.2%, respectively. Non-survivors suffered from more baseline comorbidities and experienced a more severe ceftazidime/avibactam-resistant KPC-Kp BSI presentation (i.e., both the Pitt Bacteremia and INCREMENT-CPE scores were significantly higher). Presenting with a higher Charlson Comorbidity Index, chronic kidney disease-KDIGO stage 3A or worse-having recently gone through renal replacement therapy, having suffered from an acute kidney injury following the ceftazidime/avibactam-resistant KPC-Kp BSI, and being admitted for cardiac surgery were the strongest predictors of mortality. CONCLUSION: Ceftazidime/avibactam resistance in KPC-Kp BSI easily emerged in our highly KPC-Kp endemic area with remarkable mortality rates. Our findings might provide physicians possibly actionable information when managing patients with a ceftazidime/avibactam-resistant KPC-Kp BSI.

Outcomes of 23 patients diagnosed with New Delhi metallo-beta-lactamase (NDM)-producing Klebsiella pneumoniae infection treated with ceftazidime/avibactam and aztreonam at a single center in Poland.

PURPOSE: Amongst all etiologic hospital-acquired infection factors, K. pneumoniae strains producing New Delhi metallo-ß-lactamase (KP-NDM) belong to pathogens with the most effective antibiotic resistance mechanisms. Clinical guidelines recommend using ceftazidime/avibactam with aztreonam (CZA + AT) as the preferred option for NDM-producing Enterobacterales. However, the number of observations on such treatment regimen is limited. This retrospective study reports the clinical and microbiological outcomes of 23 patients with KP-NDM hospital-acquired infection treated with CZA + AT at a single center in Poland. METHODS: The isolates were derived from the urine, lungs, blood, peritoneal cavity, wounds, and peritonsillar abscess. In microbiological analysis, mass spectrometry for pathogen identification, polymerase chain reaction, or an immunochromatographic assay for detection of carbapenemase, as well as VITEK-2 system, broth microdilution, and microdilution in agar method for antimicrobial susceptibility tests were used, depending of the pathogens' nature. CZA was administered intravenously (IV) at 2.5 g every eight hours in patients with normal kidney function, and aztreonam was administered at 2 g every eight hours IV. Such dosage was modified when renal function was reduced. RESULTS: KP-NDM was eradicated in all cases. Four patients (17.4%) died: three of them had a neoplastic disease, and one - a COVID-19 infection. CONCLUSION: The combination of CZA + AT is a safe and effective therapy for infections caused by KP-NDM, both at the clinical and microbiological levels. The synergistic action of all compounds resulted in a good agreement between the clinical efficacy of CZA + AT and the results of in vitro susceptibility testing.

In vitro and in vivo activity of ceftazidime/avibactam and aztreonam alone or in combination against mcr-9, serine- and metallo-ß-lactamases-co-producing carbapenem-resistant Enterobacter cloacae complex.

PURPOSE: Enterobacteriaceae carrying mcr-9, in particularly those also co-containing metallo-ß-lactamase (MBL) and TEM type ß-lactamase, present potential transmission risks and lack adequate clinical response methods, thereby posing a major threat to global public health. The aim of this study was to assess the antimicrobial efficacy of a combined ceftazidime/avibactam (CZA) and aztreonam (ATM) regimen against carbapenem-resistant Enterobacter cloacae complex (CRECC) co-producing mcr-9, MBL and TEM. METHODS: The in vitro antibacterial activity of CZA plus ATM was evaluated using a time-kill curve assay. Furthermore, the in vivo interaction between CZA plus ATM was confirmed using a Galleria mellonella (G. mellonella) infection model. RESULTS: All eight clinical strains of CRECC, co-carrying mcr-9, MBL and TEM, exhibited high resistance to CZA and ATM. In vitro time-kill curve analysis demonstrated that the combination therapy of CZA + ATM exerted significant bactericidal activity against mcr-9, MBL and TEM-co-producing Enterobacter cloacae complex (ECC) isolates with a 100% synergy rate observed in our study. Furthermore, in vivo survival assay using Galleria mellonella larvae infected with CRECC strains co-harboring mcr-9, MBL and TEM revealed that the CZA + ATM combination significantly improved the survival rate compared to the drug-treatment alone and untreated control groups. CONCLUSION: To our knowledge, this study represents the first report on the in vitro and in vivo antibacterial activity of CZA plus ATM against CRECC isolates co-harboring mcr-9, MBL and TEM. Our findings suggest that the combination regimen of CZA + ATM provides a valuable reference for clinicians to address the increasingly complex antibiotic resistance situation observed in clinical microorganisms.

Evolution, control and success of combination therapy with Ampicilin-sulbactam/Ceftazidime-Avibactam during a Carbapenem-Resistant Acinetobacter baumannii outbreak in burn Intensive Care Unit.

We present our findings on interpatient transmission, epidemic control measures, and the outcomes of a series of ten critically ill burn patients who were either colonized or infected with carbapenem-resistant Acinetobacter baumannii (CRAB). None of the five infected patients achieved clinical cure, and all experienced relapses. Microbiological failure was observed in 40% of the infected patients. The isolated CRAB strains were found to carry blaOXA-23 and armA resistance genes. Despite the lack of clinical cure, all five infected patients survived and were discharged from the Burn Intensive Care Unit.

Ceftazidime-avibactam versus polymyxins in treating patients with carbapenem-resistant Enterobacteriaceae infections: a systematic review and meta-analysis.

OBJECTIVE: Carbapenem-resistant Enterobacteriaceae (CRE) pose a significant threat to human health and have emerged as a major public health concern. We aimed to compare the efficacy and the safety of ceftazidime-avibactam (CAZ-AVI) and polymyxin in the treatment of CRE infections. METHODS: A systematic review and meta-analysis was performed by searching the databases of EMBASE, PubMed, and the Cochrane Library. Published studies on the use of CAZ-AVI and polymyxin in the treatment of CRE infections were collected from the inception of the database until March 2023. Two investigators independently screened the literature according to the inclusion and exclusion criteria, evaluated the methodological quality of the included studies and extracted the data. The meta-analysis was performed using RevMan 5.4 software. RESULTS: Ten articles with 833 patients were included (CAZ-AVI 325 patients vs Polymyxin 508 patients). Compared with the patients who received polymyxin-based therapy, the patients who received CAZ-AVI therapy had significantly lower 30-days mortality (RR = 0.49; 95% CI 0.01-2.34; I2 = 22%; P < 0.00001), higher clinical cure rate (RR = 2.70; 95% CI 1.67-4.38; I2 = 40%; P < 0.00001), and higher microbial clearance rate (RR = 2.70; 95% CI 2.09-3.49; I2 = 0%; P < 0.00001). However, there was no statistically difference in the incidence of acute kidney injury between patients who received CAZ-AVI and polymyxin therapy (RR = 1.38; 95% CI 0.69-2.77; I2 = 22%; P = 0.36). In addition, among patients with CRE bloodstream infection, those who received CAZ-AVI therapy had significantly lower mortality than those who received polymyxin therapy (RR = 0.44; 95% CI 0.27-0.69, I2 = 26%, P < 0.00004). CONCLUSIONS: Compared to polymyxin, CAZ-AVI demonstrated superior clinical efficacy in the treatment of CRE infections, suggesting that CAZ-AVI may be a superior option for CRE infections.

Ceftazidime-avibactam alone or in combination with Aztreonam versus Polymyxins in the management of carbapenem-Resistant Klebsiella pneumoniae nosocomial Infections (CAPRI study): a retrospective cohort study from South India.

INTRODUCTION: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections commonly cause hospital-acquired infections. The study aimed to compare the outcomes of CRKP infections between patients receiving ceftazidime avibactam +/- aztreonam and polymyxins in a hospital setting with a high prevalence of New Delhi Metallo Beta Lactamase production. METHODS: We conducted a retrospective cohort study from January 2020 to September 2022 in critically ill adult patients admitted to a non-COVID-19 medical intensive care unit with CRKP infection. The patients were followed up for a total of 30 days or death, whichever was later. RESULTS: Of a total of 106 patients included in the study, 65 patients received polymyxins and 41 patients received ceftazidime-avibactam +/- aztreonam. Higher 30-day mortality was noted in the polymyxin group (56.9% vs. 29.2%, P = 0.005). The mean time to event (mortality) in ceftazidime-avibactam +/- aztreonam was 23.9 + 1.5 days which was significantly higher compared to polymyxins (17.9 + 1.2 days, p = 0.006). On Cox regression analysis, after adjusting for the covariates, the hazard ratio for time to event with the use of polymyxin was 2.02 (95% CI: 1.03-3.9). CONCLUSION: Ceftazidime-avibactam + aztreonam is possibly associated with better clinical outcomes in patients infected with CRKP.

Ceftazidime-related neurotoxicity in a patient with renal impairment: a case report and literature review.

PURPOSE: We present the case of a 67-year-old woman with severely reduced renal clearance suffering from ceftazidime-induced encephalopathy. Subsequently, we search the literature to review and describe the neurotoxicity of ceftazidime. METHODS: A search string was developed to search PubMed for relevant cases from which relevant information was extracted. Using the collected data a ROC analysis was performed in R to determine a neurotoxicity threshold. RESULTS: Our patient suffered from progressive loss of consciousness and myoclonic seizures, with improvements noted a few days after discontinuation of treatment. The dose was not appropriately reduced to take into account her reduced renal function. The highest ceftazidime concentration recorded was 234.9 mg/mL. Using the Naranjo score we found a probable relationship between our patient's encephalopathy and ceftazidime administration. In the literature we found a total of 32 similar cases, most of which also had some form of renal impairment. Using our collected data and ceftazidime concentrations provided in the literature, a ROC analysis provided a neurotoxicity threshold of 78 mg/L for ceftazidime neurotoxicity. CONCLUSION: Ceftazidime-related neurotoxicity is a known issue, especially in patients with severe renal impairment. Yet no concrete toxicity threshold has been reported so far. We propose the first toxicity threshold for ceftazidime of 78 mg/L. Future prospective studies are needed to validate and optimize the neurotoxicity threshold as upper limit for ceftazidime therapeutic drug monitoring.

Azithromycin regulates bacterial virulence and immune response in a murine model of ceftazidime-treated Pseudomonas aeruginosa acute pneumonia.

Pseudomonas aeruginosa (PA) remains one of the leading causes of nosocomial acute pneumonia. The array of virulence factors expressed by PA and the intense immune response associated with PA pneumonia play a major role in the severity of these infections. New therapeutic approaches are needed to overcome the high resistance of PA to antibiotics and to reduce the direct damage to host tissues. Through its immunomodulatory and anti-virulence effects, azithromycin (AZM) has demonstrated clinical benefits in patients with chronic PA respiratory infections. However, there is relatively little evidence in PA acute pneumonia. We investigated the effects of AZM, as an adjunctive therapy combined with ceftazidime (CAZ), in a murine model of PA acute pneumonia. We observed that the combined therapy (i) reduces the weight loss of mice 24 h post-infection (hpi), (ii) decreases neutrophil influx into the lungs at 6 and 24 hpi, while this effect is absent in a LPS-induced pneumonia or when PA is pretreated with antibiotics and mice do not receive any antibiotics, and that (iii) AZM, alone or with CAZ, modulates the expression of PA quorum sensing regulators and virulence factors (LasI, LasA, PqsE, PhzM, ExoS). Our findings support beneficial effects of AZM with CAZ on PA acute pneumonia by both bacterial virulence and immune response modulations. Further investigations are needed to clarify the exact underlying mechanisms responsible for the reduction of the neutrophils influx and to better discriminate between direct immunomodulatory properties of AZM, and indirect effects on neutrophilia resulting from bacterial virulence modulation.

Intraperitoneal vancomycin plus levofloxacin for the treatment of peritoneal dialysis-related peritonitis in patients with no response to cefazolin plus ceftazidime.

INTRODUCTION: Peritoneal dialysis-related peritonitis (PDRP) should be treated as soon as possible by an empirical regimen without waiting for effluent bacterial culture results. We retrospectively investigated patients treated with vancomycin plus levofloxacin as a treatment regimen if there was no response to cefazolin plus ceftazidime. MATERIALS AND METHODS: We collected records of adult patients with PDRP from January 1, 2013, to November 30, 2020. The characteristics of episodes of PDRP with no response to cefazolin plus ceftazidime treated by intraperitoneal (IP) injection of vancomycin plus levofloxacin were analyzed. RESULTS: 118 episodes of PDRP were recorded, among which 115 episodes were treated with IP antibiotics. 93 episodes were treated with cefazolin plus ceftazidime. In 38 episodes, treatment was switched to IP injection of vancomycin plus levofloxacin if there was no response to cefazolin plus ceftazidime. 26/38 (68.4%) episodes were cured by vancomycin plus levofloxacin. Fever, diabetes, fasting glucose, a decrease in effluent leukocytes on day 3 and day 5, and Charlson Comorbidity Index (CCI) scores were significantly different between uncured and cured episodes. No variable was associated with treatment failure after multiple logistic regression. Fever, diabetes, a decrease in effluent leukocytes on day 3, and CCI score were associated with treatment failure after univariable logistic regression. CONCLUSION: Vancomycin plus levofloxacin may be effective if patients are not responsive to cefazolin plus ceftazidime.

Ceftazidime-avibactam in the treatment of bacteremia due to carbapenem-resistant gram-negative bacteria in hematological patients: Experience in a single center.

INTRODUCTION: Limited experience exists with ceftazidime-avibactam (CAZ-AVI) in treating bacteremia caused by carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) in hematological patients. METHODS: We performed a single-center, retrospective, observational study including patients who received CAZ-AVI for bacteremia due to CRE or CRPA between 2018 and 2022. The primary outcome was 30-day survival. We conducted a multivariable analysis to identify predictors of survival. RESULTS: 56 patients were included and 57 (41 CRE and 16 CRPA) strains were isolated. 35 strains produced carbapenemase, including 25 metallo-beta-lactamase (MBL) and 10 serine-beta-lactamase. 48 patients (85.7 %) received combination therapy. All patients with MBL-CRE bacteremia (n = 24) received combination therapy with aztreonam (AZT). The susceptibility rates to CAZ-AVI were only 26.8 % (11/41) in CRE and 80.0 % (8/10) in CRPA. The 30-day survival rates were 85.0 % (34/40) in the CRE group and 81.3 % (13/16) in the CRPA group. In patients with MBL-CRE bacteremia, the 30-day survival was as high as 91.7 % (22/24) due to combination with AZT. Ceftazidime did not influence the activity of aztreonam-avibactam against MBL-CRE in-vitro. Multivariable cox analysis revealed neutropenia >14 days (P = 0.002, HR: 34.483, 95%CI: 3.846-333.333) and a higher Pitt bacteremia score (P = 0.005, HR: 2.074, 95%CI: 1.253-3.436) were risk factors for 30-day survival. CONCLUSIONS: CAZ-AVI is highly effective in treating bacteremia due to CRPA and serine-beta-lactamase CRE. The combination of avibactam with AZT is highly effective in treating bacteremia due to AZT-resistant MBL producers.

Therapeutic insights: Use of ceftazidime-avibactam in pediatric patients.

BACKGROUND: The increasing worldwide prevalence of multidrug-resistant (MDR) bacteria underscores the pressing demand for innovative therapeutic solutions. Ceftazidime-avibactam (CAZ-AVI) represents a promising new drug combination that has received approval for specific infection types. However, there is limited information regarding its application in pediatric patients. METHODS: This study investigates the effectiveness and adverse reactions associated with CAZ-AVI treatment in pediatric patients with life-threatening infections caused by MDR pathogens. The study was conducted at a tertiary children's hospital between December, 2021 and July, 2023. RESULTS: A total of 21 patients with life-threatening infections caused by MDR pathogens were enrolled in the study. All patients had underlying medical conditions: 10 had cerebral palsy, four had congenital neurometabolic disease, two had Nieman-Pick disease, two had cystic fibrosis, two had primary immunodeficiency, and one had leukemia. Among these, 12 patients had tracheostomies. Eight patients received CAZ- AVI monotherapy, and 13 patients received combination therapy. Microbiological eradication was achieved in 18 patients (85.7%), and a clinical response was observed in 20 patients (95.2%). Two patients (9.5%) experienced relapse with the same bacteria. One patient developed anaphylaxis, and one patient had elevated creatine phosphokinase levels that normalized following discontinuation of treatment. One patient died during the study period due to gastrointestinal bleeding. CONCLUSIONS: Ceftazidime-avibactam may be a promising new drug option for the treatment of life-threatening infections caused by MDR Gram-negative microorganisms in pediatric patients. However, further studies with larger case series are needed to further evaluate the efficacy and safety of CAZ-AVI in this population.